Plumbagin accelerates serum albumin's amyloid aggregation kinetics and generates fibril polymorphism by inducing non-native β-sheet structures

• Published in: Biochimica et biophysica acta. Proteins and proteomics 2024-09, Vol.1872 (5), p.141028, Article 141028
• Main Authors: Chauhan, Chanchal, Singh, Poonam, Muthu, Shivani A., Parvez, Suhel, Selvapandiyan, Angamuthu, Ahmad, Basir
• Format: Article
• Language: English
• Subjects: Amyloid fibrils; Biophysical chemistry; Conformational switch; Ligand-protein binding
• ISSN: 1570-9639; 1878-1454; 1878-1454
• DOI: 10.1016/j.bbapap.2024.141028

The ligand-induced conformational switch of proteins has great significance in understanding the biophysics and biochemistry of their self-assembly. In this work, we have investigated the ability of plumbagin (PL), a hydroxynaphthoquinone compound found in the root of the medicinal plant Plumbago zeylanica, to modulate aggregation precursor state, aggregation kinetics and generate distinct fibril of human serum albumin (HSA). PL was found to moderately bind (binding constant Ka ∼ 10−4 M−1)) to domain-II of HSA in the stoichiometric ratio of 1:1. We found that PL-HSA complex aggregation was accelerated as compared to that of HSA aggregation and it may be through an independent pathway. We also detected that fibril produced in the presence of PL is wider in diameter, contains a higher amount of β-sheet (∼18%) and disordered (∼46%) structures, and is less stable. We concluded that the acceleration of aggregation reaction and generation of fibril polymorphism was mainly because of the higher extent of unfolding and high content of non-native β-sheet structure in the aggregation precursor state of PL-HSA complex. This study offers opportunities to explore the ability of ligand binding to modulate aggregation reactions and generate polymorphic protein fibrils. •Ligand-induced conformational switch of proteins modulates their self-assembly.•Our study focused on plumbagin's ability to regulate HSA fibrillation.•Plumbagin accelerated fibrillation kinetics and generates polymorphism of fibrils.•PL-binding did so by variation in conformations of the precursor state.